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Патент USA US3038002

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United States Patent 0
Patented June 5, 1962
an indole derivative, in which Cl, Br, I, or N02 is sub
stituted in 5- and/ or 7-position, by subsequent or alterna
tive treatment with a halogenating and/ or nitrating agent
and subsequent action of an alkaline agent. According
Jan Thesing and Gunther Mohr, Darmstadt, and Gunther
Semler, Heppenheim an der Bergstrasse, Germany, as
siguors to Rutgerswerke~Aktiengesellschait, Frankfurt
am Main, Germany
to a modified embodiment of the invention the indoline
2-sulfonic acid, which may be acylated, is converted by
No Drawing. Filed July 18, 1960, Ser. No. 43,278
Claims priority, application Germany Aug. 1, 1959
2 Claims. ((31. 260—319)
This invention relates to the preparation of substitution
products of indole and it has particular relation to the
preparation of indoles which are substituted in the ben
zene ring.
, It has been known that in the indole system the hetero
cyclic pyrrole ring is essentially more reactive to electro
philic substitutions-eg. halogenation, nitration, sulfona
tion, Friedel-Crafts reaction--than the benzene ring.
treatment with S2Cl2 and subsequent treatment with an
alkaline agent into 5,5’-diindolyldisul?de. If desired, the
latter can be split by a conventional reducing method with
hydrogenation to S-mercapto-indole.
Nitration of a compound of the above general Formula
I, can be carried out according to methods which are con
ventional in aromatic substitutions, e.g. by the action of
.a nitrating acid mixture. Thereby, ?rst a mixture of the
5- and 7-substitution product is obtained, which can be
separated eg by distillation with steam. Under suitable
reaction conditions-—-e.g. extended period of treatment or
increased concentration of the nitrating acid—the 5,7-di
Therefore, in carrying out these substitutions a reaction
nitro-compound can also be prepared.
of the substituent in the pyrrole ring can be generally 20 By the action of acetyl nitrate on compounds of the
observed. For this reason the preparation of indoles sub
above general Formula I, in a smooth reaction a nitro
stituted in the benzene ring could be performed by indirect
derivative substituted exclusively in the 7-position can be
methods only.
obtained and the resulting product can be converted by
It has been hitherto necessary either to use as starting
subsequent treatment with alkali into 7-nitro-indole. This
material a phenyl hydrazone substituted in the nucleus,
reaction can be carried out, for example in acetic anhy
which was subjected to indole synthesis according to
dride as the solvent.
Fischer, or indole was hydrogenated to indoline, which
Furthermore, a salt of N-acyl-indoline-Z-sulfonic acid,
was then subjected to the desired substitution and the sub
‘which is already halogenated or nitrated in the 5-position,
stituted indoline was then dehydrogenated to the corre
can be subjected to a subsequent nitration or halogenation.
sponding indole compound. The preparation of the sub E23 O In proceeding in this manner, in both cases a disubsti
stituted phenyl hydrazone as well as the procedure calling
' tuted indole derivative is obtained, which is differently sub
for hydrogenation and dehydrogenation, are relatively
troublesome and the yields of these procedures are unsatis
factory. Moreover, said ?rst mentioned method is not
stituted (halogenated and nitrated) in the 5- and 7-position.
The introduction of a S-bromo substituent can be e.g.
brought about by the action of elementary bromine on
suitable for the preparation of indoles which are not sub- 0..‘ Cl a compound of the above Formula I.
stituted in the pyrrole ring. (H. R. Snyder and C. W.
Smith, J. Amer. Chem. Soc. 65, 2452 (1943).)
S-iodo-indole can
be prepared by the action of iodine which can be produced
e.g. from potassium iodide and iodine monochloride.
Chloroindoles can be prepared by reacting a compound
It ‘has now been found that reactions consisting of sub
stitutions in the benzene ring of the indole system can be
of the above Formula I with chlorine water, or an alkali
carried out if the aromatic character of the pyrrole ring 40 hypochlorite, or with chlorine in glacial acetic acid.
in the indole molecule is temporarily canceled by the
Thereby a mixture of chloro-indole derivatives substituted
formation of an indole-2-sulfonic acid (hydrogen suliite
by chlorine in the 5- and/ or 7-position are formed, which
compound of indole). A sulfonic acid salt of indoline
can be subsequently separated into the individual compo- _
reacts in the substitution reactions like an o-substituted
nents of the mixture.
derivative of aniline. The amino~group of the indole ring 45
Splitting oil‘ of the acyl group protecting the amino
is preferably blocked according to conventional methods,
group and of the hydrogen sul?te is preferably carried out
for example by acylation.
According to the present invention, it is possible to sub
stitute an indoline-Z-sulfonic acid salt of the Formula I
by treatment with an alkaline agent in one reaction step.
For example, concentrated potassium hydroxide or con
centrated sodium hydroxide, is suitable for this reaction.
The indoles substituted in the benzene ring according
to the present invention can be utilized for the preparation
of further indole derivatives. For example, by the re
duction of the nitro-group S-amino indole and from the
latter derivatives N-substituted in the amino-group can be
(I) 55 prepared, according to conventional methods. From com
pounds which correspond to the above Formula I and are
wherein R stands for H or acyl and Me is a metal ion,
halogenated in the 5-position, S-cyan-indole can be easily
preferably Na or K, by halogenating and/ or nitrating in
the para and/ or ortho-position to the amino group. Sub
The salts of indoline-Z-sulfonic acid used as starting
sequently, by treatment with an alkaline agent the hydro 60 materials are easily obtainable. For example, the alkali
gen snl?te and, if desired, simultaneously the protecting
salts can be obtained by reacting indole with alkali hydro
acyl group can be split off. In this manner, indoles sub
gen sul?te.
stituted by Cl, Br, I and/or N02 in 5 and/or 7 position
The N~acyl-indoline-sulfonic acid salts are obtained
can be obtained in a simple manner. Furthermore, by
from the corresponding indoline-Z-sulfonic acid salts by
treatment of a compound of the Formula I with S2Cl2 65 conventional acylation methods. Examples of the latter
and subsequently with an alkaline agent, 5,5’ di-indolyldi
are the conventional reactions with acetic anhydride, acetyl
sul?de and by reduction of the latter S-rnercapto-indol can
chloride, benzoyl chloride, p-toluene sulfonic acid chloride
be prepared.
and with similar compounds. The N-acyl residues can be
Thus, the present invention relates to a process for pre
later easily removed by simple treatment with alkali ac
paring indoles substituted in the benzene ring. In this
cording to conventional methods.
process a salt, preferably an alkali salt, of an indoline-Z
The compounds prepared according to the present in
sulfonic acid, which may be N-acylated, is converted into
' vention can be used not only as starting material for fur
pended in one liter of water and distilled with steam. The
ther derivatives of indole but they are also important ,
distillate thus obtained is repeatedly extracted with ether
and therether solution is evaporated after drying over so
intermediate products for the preparation of pharmaceutic
dium sulfate. The residue yields, after being subjected
(a) Preparation of the sodium salt of indoline-Z-sul
U! to chromatography in a column of aluminium oxide, by
elution with a benZene-cyclohexane mixture (2:1) 7-nitro
indole in the form of yellow needles having a melting point
ionic acid.—50 grams of indole are dissolved in 70 com.
of ether and shaken with a mixture of 150 ccm. of com
of. 94°—97° C. The still hot residue of the steam distilla
tion is sucked o?. From the ?ltrate upon cooling the
of water and 300 ccm. of alcohol of 96%, for 10 hours.
10 S-nitro-indole crystallizes in almost pure form. It is sep
The colorless crystals are separated by suction, Washed
arated by ?ltration and dried. A further amount of S-ni
mercial soduim hydrogen sul?te solution ‘of 40%, 50 ccm.
with methanol and ether and dried.
(b) Preparation of the sodium. salt of N-acezyl-in
- tro-indole can be recovered by boiling with water the
residue found on the suction ?lter. By recrystallizing the
doline-Z-sulfonic acid-15 grams of the sodium salt of in
doline-Z-sulfonic acid, 15 grams of sodium hydrogen sul
?te and 150 ccm. of acetic acid anhydride are subjected
to fast stirring at 50° C. After about 1/2 hour the mixture
starts to swell. After a total period of 3 hours the prod
S-nitro-indole from benzene-cyclohexane, yellow needles
having a melting point of l40°~l41° C. are obtained.
As examples of the. various uses of products prepared
according to the present invention the following may be
mentioned: 5-bromoindole can be used as an interme
not is sucked off and can be used in crude condition in the '
subsequent reactions.
(0) Preparation .of 5-bromo-indole.-Sodium salt of
N-acetyl-indoline-Z-sulfonic acid freshly prepared from
diate product in the preparation of harmane (see I. Am.
20 Chem. Soc, vol. 70, page 225 (1948)); 7-nitroindole can
10 grams of sodium salt of indoline-Z-sulfonic acid, is dis
I solved under cooling and stirring in 50 ccm. of water and
be used for preventing the growth of a lactobacillus (see
J. Organic Chemistry,ivol. 22, page 84 (1957) ); S-chloro
indole and 7-chloroindole can be used for biological in
vestigations (see J. Chem. ‘Soc. 1955, page 3501).
separated from undissolved material by ?ltration. In the 25 It will be understood from the above that this inven
tion is not limited to the speci?c substances, steps, propor
dropwise at 0°—5° C. into the solution. Subsequently, the
tions and other conditions and procedures speci?cally de
reaction mixture is stirred at 0° C. for one hour, stirred
scribed above and can be carried out with various modi
at room temperature for a further hour, diluted with 200
?cations. For example, while Me stands preferably for
course of 1 hour- 15 grams of bromine are introduced
com. of water and the clear solution is rendered alkaline
oif and washed with water. After recrystallization from
alcohol of 30-40%, or after puri?cation by steam distil
lation, colorless needles having a melting point of
Na or K, it may also stand for other metal ions, such as
NH4, ‘Ca, or a heavy metal. These and other modi?ca
tions may be made without departing from the scope of
the invention as de?ned in the appended claims.
What is claimed is:
1. In a process for preparing chloro-, bromo-, ionic
90°—9'1° C. are obtained.
and nitro-derivatives of indole, which contain in the ben
at 20°-—30° C. with sodium hydroxide solution of 20%.
' After standing over night the crystals formed are sucked
Preparation‘ of 5—i0‘d0-ind0le.--80 grams of the sodium
zene ring of the indole molecule a substituent selected
from the group consisting of Cl, Br, ‘I, and --NO2 in a
position selected from the group consisting of 5 and 7
salt of indoline-Z-sulfonic acid are acetylated in the man
ner described in the above Example 1(1)). The sodium 40 positions (a) the step of mixing indole in solution with
Mel-I803 in order to form a, compound of the formula
salt of N-acetyl-indoline-2-sulfonic acid is dissolved under
cooling in 300 ccm. of water'and ?ltered. Subsequently
40 grams of potassium iodide are added and during 10
minutes 40 ccm. of iodine monochloride are dropwise
added at 0°-4° C. The mixture is then stirred for one 45
hour under cooling with ice, and then stirred for an addi
tional hour at room temperature, 1500 ccm. of water are
added, the precipitate formed is separated by ?ltration and
in which Me stands for a cation selected from the group
the ?ltrate is rendered alkaline with concentrated sodium
consisting of Na, K, NH; and Ca; (b) mixing this com—
hydroxide solution at 20° C. After standing over night 50 pound with an N-acylating agent selected from the group
the precipitate formed is sucked off, washed with water,
consisting of acetyl- benzoyl- and p-toluene sulfonic acid
and dried. ' Needles of a weak yellow color are obtained,
radicals in order to block ‘the amine group of the indole;
which are puri?ed by re-precipitation with water from
(c) reacting the compound resulting in (b) with the sub
ethanol solution and have then a melting point of
stituent to be introduced into positions selected from the
99400“ C.
55 above de?ned group; and (d) subjecting the resulting sub
stitution product to treatment with an alkali hydroxide
in order to split ed the acyl group and the hydrogen sul
Preparation of 5- and 7-nilr0 ind0le.-—-The sodium salt.
?te to form a product of the formula
of N-acetyl-indoline-2-sulfonic acid prepared from 15
grams of the sodium salt of indoline-Z-sulfonic, acid in
the manner described above, is disoslved under good cool 60
ing and with stirring in 200 ccm. of water. To the ?l
tered solution at 0°—5° C. a cold mixture of 50 ccm. of
nitric acid of 65% with 50 ccm. of concentrated sulfuric
acid are dropwise added within 30 minutes. The tempera
ture should thereby remain below 0° C. Subsequently,
the reaction mixture is stirred for one hour at 0° C. and
for an additional hour at room temperature, then diluted
with 150 ccm. of water and rendered alkaline with con
centrated sodium hydroxide solution under cooling below
40° C. At a change point the previously light-brown solu 70
tion suddenly becomes dark-brown and yellow crystals
start to seperate.
After standing over night the crystals .
wherein X is selected from the group of substituents de
?ned above.
2. A process as claimed in claim 1, in which Me stands
for the sodium ion and the acetyl-radical is used as the
N-acylating agent.
References Cited in the ?le of this patent
Gall et al.: I. Organic Chem, vol. 20, pages 1538-1544
are sucked off and washed with a small quantity of cold
Tomino: J. Pharm. Society (Japan), vol. 77, pages
water. The precipitate consists of a mixture of S-nitro
indole with 7-nitro-indole. The still wet mixture is sus 75 1087-1093 (1957).
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